The long-term objective of this proposal is to understand the brain's natural pain-inhibitory capacity. It is felt that this objective can best be met by pursuing studies of stimulation-produced analgesia (SPA) and stress-induced analgesia (SIA) in rats. Because sub-systems of SPA and SIA are now known to exist, some mediated by opioid peptides, others, not, it is felt that particularly significant progress can now be made in defining the anatomy and neurochemistry of these systems. SPA and SIA are tools for investigating mechanisms of endogenous analgesia that have proven useful so far and should prove more useful still now that their separate substrates are beginning to be understood. The specific aims of this proposal are: 1. To investigate the neurochemistry of opioid and nonopioid forms of SPA and SIA by studying the susceptibilities of each form to modification by certain drugs. Using standard analgesiometric tests such as the rodent tail-flick assay, the effects of drugs known to modify central serotonin and histamine systems will be studied. 2. To investigate the anatomy of opioid and nonopioid forms of SPA and SIA by studying the effects on the different forms of SIA of lesions in those areas of the periaqueductal gray matter known to be important in mediating opioid and nonopioid forms of SPA. 3. To investigate peripheral vs. central and cerebral vs. spinal sites of opioid binding concerned with the several opioid forms of SPA and SIA by making discrete microinjections of opiate antagonists into ventricular and spinal areas. 4. To investigate the effects of anesthesia on SPA and to study SPA's effects on the immune system (natural killer cell cytotoxicity). 5. To investigate the bulbar relay mediating the different forms of SIA by making bulbar lesions. Studies of SPA have already led to successful clinical trials with deep brain stimulation for pain relief in humans. It is hoped that continued studies of SPA and SIA will assure further progress in this direction by disclosing both noninvasive means of activating natural analgesia systems and nonopioid mechanisms lacking unwanted opiate effects.